Management of small renal masses–update 2011

Rationale: The management of renal parenchymal tumors has known many changes over time, a trend that continues today, as a result of technological advances, clinical research and improved diagnostic and therapeutic tools. Unfortunately, conventional cancer treatments–chemotherapy and radiotherapy have proven ineffective and modern approaches such as immunotherapy, angiogenesis inhibitors, though they enjoyed an initial enthusiasm, subsequent studies have shown limited and controversial effects. Thus, surgery remains the gold standard therapy for this type of cancer. The options for the treatment of RCC are numerous, with options that have advantages and disadvantages, with oncological results, in most cases, positive at five years and with different impact on cancer specific survival. It is difficult to compare the results, as these are different techniques with various instruments and intraoperative steps, with more questionable inclusion criteria, selection biases and prosecution, with a tendency for preferential enrollment, different reasons to why randomized prospective studies have not been performed until today. Objective: This article is a review of the diagnosis and methods of treatment of small renal masses 2011. Conclusion: At the beginning of the new millennium, kidney cancer, with all the arsenal of techniques and methods of ablative surgery, remains a potentially fatal disease for a high percentage of patients, and the decision to choose a treatment or another should be taken with responsibility, depending on currently existing medical records, the degree of expertise and not based on subjective or other non–standard parameters.


Introduction
The management of renal parenchymal tumors has known many changes over time, a trend that continues today as a result of technological advances, clinical research and improved diagnostic and therapeutic tools.
Unfortunately, conventional cancer treatmentschemotherapy and radiotherapy have proven ineffective and modern approaches such as immunotherapy, angiogenesis inhibitors, though they enjoyed an initial enthusiasm, subsequent studies have shown limited and controversial effects. Thus, surgery remains the gold standard therapy for this type of cancer.
Aggressive surgical approach to remove the whole tumor burden, here meaning both primary lesion and its extension -venous, lymphatic or metastaticremains the only effective method that can ensure the cure, or, in some cases, the treatment of severe symptoms in order to increase the quality of life of these patients.
During the first half of the twentieth century, simple nephrectomy was the standard treatment of renal parenchymal tumors. The first radical nephrectomy with removal of the kidney, adrenal gland and fat tissue within the Gerota's fascia was reported by Mortensen in 1948 [1]. In 1960, Robson and colleagues added the retroperitoneal lymph node dissection to the radical nephrectomy, reporting high rates of survival at 5 years [2,3].
Although the incidence of kidney cancer has increased significantly worldwide in recent years, most tumors are detected in early stages, when the conservative treatment can be performed with curative aim. Extensive use of abdominal ultrasound plus evaluation of the detected lesions by computer tomography, represent the diagnostic imaging tools that had the greatest impact in the immediate change of the clinical evolution of renal tumors. Thus, the concept of incidentaloma arose, because kidney cancer is often detected incidentally in countries with a developed medical system.
In 1884, Wells performed the first partial nephrectomy for a kidney fibrolipoma and in 1887 Czerny did this type of intervention in a patient with solitary kidney (imperative indication). In 1950, Vermooten performed the first partial nephrectomy in a patient with normal controlateral kidney (elective indication). Subsequently, surgical technique has evolved, but it still remains a challenge, especially for central tumors or in patients with imperative indications. Although these operations have been globally popularized and recommendations have been established and published in medical practice guidelines, a study published in the U.S. paradoxically showed, that an extremely low number of partial nephrectomy are made even for small renal masses [4].
Percutaneus ablative techniques (cryotherapy and radiofrequency ablation) have been improved in the last decade, with deeper knowledge of cellular metabolism and implications of low temperatures, i.e. ultrasounds on tumor cells. However, long-term results are contradictory, with still unacceptable risks related to recurrence and metastatic progression of the disease.
Active surveillance, a relatively new concept in renal cancer, has an absolute indication in the presence of major comorbidities that prohibit surgical or percutaneous ablative techniques for patients with reduced life expectancy, with low performance status or patients who refuse surgery (relative indication).
Although the depth of tumor progression mechanisms has evolved and the urologist's armamentarium has been diversified, the question "why and how to treat all the kidney tumors?" still stands.
Small renal tumors, defined as T1a in the international TNM staging, have a risk of death of 5% at 5 years without treatment and in T2 stage associates a risk of death of 27% over the same period of follow-up. On the other hand, approximately 30% of renal tumors, less than 2 cm are benign, so they are not life-threatening [5]. In a study published in the Journal of Urology in 2006 Remzi reported that 11% of the tumors less than 3 cm are actually pathological pT3a, 5% are G3 as histopathological grading and 2.5% are metastatic at diagnosis [6], in other words trying to differentiate the aggressive from, the mild forms still remain a challenge for the urologist today.
All these data confirm the lethal potential of small renal tumors, the possibility of local and systemic progression, with no mathematical correlation to the size.

What are small renal masses (SRM) and how do we diagnose them properly?
Imaging can provide objective answers to the clinician's questions such as whether it is a tumor or not and its degree of development, relationship with adjacent structures, presence or absence of metastatic sites. A special feature is the anatomical position of this type of tumors, most accurately described by the investigation that can access the retroperitoneum, such as computer tomography or magnetic resonance imaging.
Due to its accessibility and safety, renal ultrasonography became the first imaging method, essential in evaluating a patient with abdominal symptoms and the examination of a seemingly healthy individual who presents for a routine checkup or in postoperative protocols. The dependence on the expertise of physicians is the main disadvantage of ultrasound, plus the absence of direct information on renal function and excretory routes except for indirect signs such as uretero-and / or hydronephrosis.
Intraoperative ultrasonography for detecting multicentric tumors or the parenchymal extension may be indicated in conservative renal surgery, but is not routinely applied.
Renal ultrasound is not considered an ideal imaging method for screening because the lesions smaller than 2 cm may remain undiagnosed, but it can be used on selected groups of risk patients and asymptomatic elderly population [7].
Doppler ultrasound can accurately certify the presence of tumor thrombus in the inferior vena cava and the cranial extension, including right heart cavities, in which the transoesophageal echocardiography is mandatory.
In fact, any renal mass with solid characters in the ultrasound exam has indication for contrast enhanced computer tomography examination, which is currently the election method for the detection, characterization and staging of renal masses. Spiral computer tomography with 5 mm sections allows the identification and correct description of renal lesions with a minimum size of 1.5 cm. We can use relatively thin slices of 2.5 mm in the kidney.
Not all kidney tumors are well defined during the corticomedular phase, so the images obtained during late phase (nephrographic or excretory phase) should be included to facilitate the detection of renal masses, particularly small ones [8,9].
In addition, acquisitions in excretory phase (normally obtained after a scan delay of 3 minutes) are We consider that any difference higher than 20 HU between SRM and the surrounding parenchyma with the presence of calcifications within a solid renal mass are imaging markers that suggest malignancy [11].
Magnetic resonance imaging (MRI) is used complementary to CT imaging only in cases where we cannot perform computed tomography (chronic renal failure, contrast allergy, etc.).

Imaging SRM: is pathology correlated?
Oncocitomas could be confused with clear cell renal tumors in terms of imaging features and degree of contrast load [12].
In contrast, Cromophobe carcinomas, are much more varied in terms of levels and patterns of contrast load.
Negative densities are considered the mark of angyomiolipomas. High, homogeneous attenuation on native scan and charge on contrast have been reported in cases of angyomiolipomas, which contain more muscles fibers and less fat, or in cases of sarcomatous degeneration [13].

We have the diagnosis, how do we treat?
The goal of treatment is to cure patients of cancer, preferably saving the kidney function and, if possible, with minimal perioperative morbidity.
The choice of treatment depends on many factors, which are listed below: 1. Tumor factors -stage, tumor size, location, Fuhrman's grading, histology, presence of tumor markers and receptors; 2. Factors related to the patient: performance status (ECOG or Karnofski), age, renal function (global and controlateral kidney), cardiac function, comorbidities, surgical history, etc; 3. Local facilities: open approach, laparoscopic, robotic and opportunities for cryoablation or radiofrequency, anesthetic and ICU support; 4. Active participation of the patient to treatment (regular follow-up, appropriate compliance).
Regardless of the treatment method we choose, the patient should be informed about the risks associated with each method: hemorrhagic risk, risk of positive margins, urinary fistula, the occurrence of postoperative acute kidney injury, intraoperative conversion from a laparoscopic/robotic approach to open and the need of conversion from partial to total nephrectomy.

Treatment of SRM
The options for the treatment of RCC are numerous, with options that have advantages and disadvantages, with oncological results, in most cases, positive at five years and with different impact on cancer specific survival.
Comparing the results is difficult, as these are different techniques and with various instruments and intraoperative steps, with more questionable inclusion criteria, selection biases and prosecution, with a tendency for preferential enrollment, different reasons to why randomized prospective studies have not been performed until today.
We have three clear answers so far: 1. Conservative surgery (NSS) has won the "battle" with radical nephrectomy in the treatment of small renal tumors.
Why? a) If we perform NSS in a patient with normal controlateral kidney, we assume the probability of 20% at three years to develop chronic kidney disease (glomerular filtration rate <60 ml / min) and 65% probability for radical nephrectomy. We also have the misfortune of 5% after NSS at 3 years of having a severely reduced glomerular filtration rate (below 45 ml/min) and 36% after a total nephrectomy. In a study published by Thompson et al. in the Journal of Urology in 2008, patients with ages less than 65 years old, who had radical nephrectomy for SRM, had a lower overall survival rate than patients who underwent NSS. Thus, mortality from cancer in certain situations differs from that determined by other comorbidities [15]. b) At a glomerular filtration rate between 60-45 ml / min, the relative risk of death from cancer is 1.2, the relative risk for cardiovascular events is 1.4 and for hospitalization is 1.1 [16]. At a filtration rate between 45-30ml/min, the relative risk of death from cancer is 1.8, the relative risk of cardiovascular events is 2.0 and for hospitalization is 1.5 and at a filtration rate between 15-30 ml/min, the relative risk of death from cancer is 3.2, the relative risk of cardiovascular events is 2.8 and for hospitalization is 1.5. c) Overall survival at 5 and 10 years is 85.5% for radical nephrectomy and 88.9% for NSS and 10 years 68.8% and 70.9%, respectively [16].
Conclusions: The oncological results are similar for both treatment modalities for small renal tumorsclassified T1a, but NSS reduces the risk of nontumoral death and maintains the renal function (80% for NSS vs. 35% for radical nephrectomy).

The role of adrenalectomy
Adrenalectomy is not routinely indicated except for the upper pole tumors or on suspicious adrenal lesions on CT or intraoperative.
3. According to EORTC, Locoregional lymph node dissection in renal cell cancer does not increase survival rate at 10 years [17].
The report concluded that a correct lymph node dissection does not bring a higher morbidity risk for the patient and the risk of lymph node-positive in patients who did not have imaging or intraoperative suspicion is 3.3%, which, according to the authors of the study does not justify the procedure. In our experience, which includes approximately 3800 renal tumors in various stages, operated in the past 10 years, this is an inappropriate management. Routinely performing locoregional lymph node dissection induces additional expertise, which does not associate a higher morbidity, it is not time consuming and the oncological results, at least for the microscopic invasion, are excellent. This concept of radical surgery finds its counterpart absolutely in open surgery.

Open radical nephrectomy
It has represented the gold standard procedure in the treatment of renal cell cancer over the years. However, in the last decade, due to good results reported by the NSS, its indication has become secondary. Global statistics for radical nephrectomy are presented as following [18]: mean hospital stay 6 days, 5% risk of readmission, mean intraoperative blood loss 325 ml, 16% risk of transfusion, 17% perioperative morbidity, mortality 0.3%. In addition, the risk of reintervention after a radical nephrectomy is of 0.6% and local recurrence rate reported is 0.3%. Regarding the oncological outcome, cancer specific survival at 5 years reaches rates of 94-98%. Radical nephrectomy is associated with a shorter hospitalization time, few type II and III complications on the Clavien scale, but it considerably increases the mortality from noncancerous specific events.

NSS is the new gold standard for small renal tumors (SRM)
Regardless of the approach path and the available technology (open, laparoscopic, robotic), shortterm oncological results are similar, but, unfortunately, the long term are contradictory or even unpublished. The need for long-term studies in a prospective randomized fashion is imperative in order to impose new standards for the treatment of RCC.
1. Open NSS has imperative, elective indications (normal controlateral kidney, accessible tumors under 4 cm) and relative indications (kidney disease associated tumors larger than 4 cm, etc.). Early complications reported, mostly due to a warm ischemia time (WIT) higher than 20 minutes, have a rate of 13.4% and the late complications are maintained at a high rate of 32%. Oncological results are translated into the local recurrence risk of 1.4% and 0.69% rate of systemic recurrence. Cancer specific survival for small renal tumors less than 4 cm is of 98% [20]. According to Gill's study, recently published with a remarkable honesty, the functional and oncological results obtained after 800 conservative operations laparoscopically performed, are improving, warm ischemia time (WIT) is reduced with increased risk of bleeding in early pedicle declamping, but, unfortunately, do not reach the results reported by open surgery. In addition, the learning curve even after this huge number of procedures is still on the ascendant trend [23].

Laparoscopic NSS
In conclusion, laparoscopic NSS can be performed in centers of excellence, still technically difficult, and it is associated with a higher risk of complications. The need for new tools is imperative and well-managed long-term studies are required in order to establish this procedure as an indication in daily practice.

Robotic NSS
Although promoted in recent years, conservative robotic surgery is still in evaluation, with scarce medium and long-term results. Certain procedures, such as hemostasis and intracorporeal sutures are easier to perform than laparoscopy, with lower WIT. Oncological results are contradictory and time tracking of patients is still insufficient to bring this technique into standard surgical practice.

Percutaneous ablative techniques in the treatment of small renal tumors (SRM), cryotherapy and radiofrequency ablation by HIFU.
The mechanism of action involves the use of agents, which determine the precipitatation of intracellular proteins, thereby causing cell apoptosis and necrosis. Ablation uses currents generated by radiofrequency (RFA) and is indicated in tumors with certain specific locations. It obtains diffuse necrosis, with secondary injury to the surrounding tissue. On the contrary, cryoablation limits its action as it is focused only on tumor tissue.
The need to introduce these procedures in the urological arsenal derives from the daily practice, as an alternative treatment for a difficult group of patients. Thus, those with low performance status, who present multiple comorbidities or those who refuse other more invasive procedures, have proved to be candidates for ablative techniques. In addition, tumors with a low malignant potential or those who have genetic syndromes such as Von Hippel-Lindau, can be candidates for one of these procedures.
HIFU can be performed through a percutaneous or laparoscopic approach, but the paucity of studies available in the literature, along with poor functional and oncological results, maintain this technique as an experimental procedure in the treatment of RCC [26].
Cryotherapy can be performed laparoscopically (60% of the cases), percutaneously (30%) or by an open approach. Regardless of the approach path, general anesthesia and longer operative time are required, together with longer hospitalization. Between percutaneous and laparoscopic approach, looking in particular at the differences regarding the costs, the percutaneous approach is cheaper, and the transfusion risk is higher for laparoscopic approach (11% vs. 28%) [27].
The temperature at which cell death occurs depends on the type of the cell. Thus, in the kidney it is of -19.4 C. In kidney cancer it is situated at a temperature below -10C, 96% of the cells survive, reducing the percentage to 15% at -20 degrees C [28].
In addition to lowering the temperature, the time also matters, and a longer period seems to provide a better oncological status. The size of necrosis area assessed at 2 weeks, shows similar values, regardless of the needles' size used in cryoablation [29].

Fig. 4. Open NSS -intraoperative aspect ("Fundeni" Archives)
Percutaneous radiofrequency ablation is performed in 90% of cases, so it requires sedation in most cases, which brings lower operative time and overall, lower costs.

Do these procedures imply no complications?
The answer is definitely not, some of them are severe and we question ourselves whether these are minimally invasive techniques. The following are reported in literature: kidney, liver or pancreas laceration, kidney hematoma, intestinal obstruction, pieloureteral junction syndrome, urinary fistula, conversion to open surgery, etc. Overall, the rate of major perioperative morbidity for both procedures is, regardless of the approach, between 0.8 and 4% (higher for percutaneous RFA). [30] The Cryotherapy and radiofrequency ablation preserves pre-existing renal function. However, the studies analyzed, showed that 20% of the patients with chronic kidney failure who have a glomerular filtration rate below 60 ml / min, of which 15.5% had de novo CKD [31].
Long-term oncological results are scarce and contradictory; only one study has a follow-up period of 5 years on cryotherapy, the overall survival rate of 84% being reported, the cancer specific survival rate of 92% and 81% specific-disease free [32].
There are also two studies that reported data on cancer outcomes for patients treated with RFA, with a low number of individuals enrolled, with cancer specific survival rate of 94-100% and the risk of local and systemic recurrence of 5-10%, which is unacceptable from our point of view. The risk of local progression reported for cryotherapy is of 5.2% compared to 13% for radiofrequency ablation and the systemic progression of 1% and 2.5%. Regarding the risk of reablation, Lavinson et al. reported a rate between 1.3% to 8.5% for cryotherapy and RFA, respectively [33,34].
Energy ablative techniques remain an alternative to radical/conservative surgery, but the results and criteria for evaluation of treatment response are still being under evaluation. The follow-up is done purely radiologically and, in many cases, they were positive after rebiopsy, with no corresponding imaging for active tumor. After such procedures, salvage surgery is "challenging", whether we consider conservative or radical surgery.
Active surveillance, a relatively new concept in renal oncology, has an absolute indication in the presence of major comorbidities that prohibit any type of surgical approach or energy ablative techniques in patients with reduced life expectancy, with low performance status or patients who refuse surgery (relative indication).
The theory behind this procedure derives from the observation that 30% of the SRM do not grow in size, and from those that are still progressing, most of them slowly grow about 0.3 cm / year, few reaching rates higher than 1 cm/year. Also, there is no correlation between growth rate and prognosis of patients; in addition any degree of aggressiveness of the tumor cannot be forecasted based on this parameter [35].
However, there is no long-term data in order to establish the place of this method in the renal cancer therapeutic arsenal, but has a follow-up period higher than that of percutaneous ablative techniques, or even for laparoscopic NSS, and many clinicians consider active surveillance beneficial when compared to other procedures mentioned, at least from this point of view.

What do we know so far about the active surveillance of SRM?
In a study published in 2006 by Chawla, the authors report a systemic progression rate of 1% in the group studied [35]. A year later, Abou Youssif published an article, which reported that 5.7% of patients developed lung metastases during follow-up period [36], and Crispen reported in 2009 a 1.3% rate of systemic progression [37].
In conclusion, patients under active surveillance have an average risk of systemic progression of 1-2% and as a general observation, we can say that progressing tumors tend to grow faster. However, deaths during the studies were not caused by cancer, in other words, cancer specific survival was of 100%.
Unfortunately, several questions remain unanswered; one of the unknowns is when to decide to stop actively monitoring the patients and shifting them to surgical treatment. Thus, losing the window of opportunity for a radical curative therapy remains a constant concern. In addition, tumor aggressiveness, regardless of size, cannot be predicted earlier, and opponents of this method consider it hazardous to monitor this type of tumor taking into account its high risk of progression. Also, the proportion of benign lesions, which theoretically would be amenable for such therapy, is not known precisely.
When do we stop active surveillance? According to present recommendations for complex cases included in genetic syndromes (von Hippel-Lindau syndrome, etc.), active surveillance ceases when the tumor reaches 3 cm in diameter. Secondary renal tumors, with proven tumor progression in two successive evaluations, require at least caution, if not stopping of the active surveillance [37]. More subjective factors relating to the patients, their refusal to continue the monitoring and the decision to operate, must be taken into account in order to stop the surveillance and proceed to another therapeutic approach.
Renal biopsy has emerged as an effective diagnostic method and has lately improved due to the perfection of the technique itself, but also due to popularized conservative therapies. It can be performed under ultrasound guidance or under tomography, the first approach with a longer learning curve and can be technically difficult, especially in obese patients.
Depending on the manner of execution, such as needle type and the material collected, renal biopsies may be aspirative (FNA) or type core, both with high sensitivity (90%), except that the aspiration method has a lower sensitivity for Fuhrman grade and requires the interpretation from an experienced cytologist.
No major complications (transfusion, embolization, and surgical reinterventions) were reported, there are some are cited most frequently. According to an article published in 2009 by Lechevallier, kidney subcapsular hematoma is met in an alarming proportion of 44%, followed by arteriovenous fistula, pneumothorax, bowel perforation [38]. The risk of tumor seeding, urooncologists once feared has disappeared, being described in only six cases, the last one being reported in 1992.

Is renal biopsy useful?
The method has a sensitivity of 70-100%, specificity of 100%, accuracy of 90%, performance parameters that have promoted this method in clinical practice. However, we believe that these indices are overrated and the abuse of such procedures is detrimental to the patient and to the oncological management of the tumor. In addition, the nephrology and transplantation daily practice and we agree that, in a significant proportion of cases, the pathologist interpretations are ambiguous. In large studies, this percentage increases to 25% of patients and therefore biopsy is nondiagnostic and induces major confusions with a delay of treatment with curative visa [39].
We believe that renal biopsy is useful whenever afterwards, the therapeutic attitude changes or in selected cases of secondary kidney tumors, if we suspect a metastasis from another cancer or lymphoma, before energy ablation therapy or prior to treatment with angiogenesis inhibitors. However, if the tumor is smaller and more centrally located, the more chances we have for a negative biopsy. In cases of large tumors, the harvesting of tissue from the necrotic or hemorrhagic areas poses a high risk for blending that needs to be taken into consideration.
Tumor markers have been studied extensively in the pathogenesis of RCC. The results are disappointing, the need for such biochemical parameters for the diagnosis and monitoring of patients is imperative. The following markers have been reported: carbonic anhydrase, Ki67, C-reactive protein, although initially they seemed promising, they have passed on the second place, never being evaluated prospectively. Prognostic

Conclusions
The risk of local recurrence is 7 and 18 times higher for cryotherapy and radiofrequency ablation versus conservative surgery or active surveillance; in addition, recurrences require radical surgery, which is difficult to perform after ablative techniques because of secondary fibrosis [43]. A high positive biopsy rate after RFA, which has no counterpart tumor imaging (MRI), has also been reported [44].
Partial nephrectomy, with all its technical forms (open/laparoscopic, enucleation/enucleoresection vs. wedge/partial nephrectomy) has become the new gold standard for the treatment of small renal tumors, although it remains underused. Approximately 27% of RCC T1 is treated by NSS in the U.S., the rest being solved by radical nephrectomy [45]. Partial nephrectomy brings a proven level of technical difficulty, especially for tumors on anterior valve, centered, large or upper renal pole, but overall perioperative morbidity related parameters remain within acceptable limits, which are improving with experience. However, in postoperative bleeding, the risk of urinary fistula are complications which the urologist must be familiar with, as coagulation and suturing techniques have improved, a significant percentage of patients, especially those with imperative indications, unfortunately have the risk to present such unwanted postoperative events.
Ablative techniques have not yet shown efficacy in patients without major contraindications for surgery and patients who choose such treatments must be informed of all treatment alternatives. Selecting an ablative technique is risky, both in short and long term, when it comes to cancer free survival rates. Pressure applied by patients who want the therapy with the lowest physical and psychological impact and by innovative companies should not be exercised in order to radically alter the therapeutic decision. The urologist must decide which approach is more familiar to him and which one has proven the best results for the patients, not letting the medical industry determine the method instead. A quick solution, with minimal impact on the health care system and patient's quality of life, does not always cure the patient or at least provide a good oncological prognosis.
At the beginning of the new millennium, kidney cancer with all the arsenal of techniques and methods of